adj. situated or occurring inside a cell or cells.
Causes The condition is usually due to faulty metabolism of fat, resulting in the production of beta-hydroxybutyric and acetoacetic acids. It occurs in DIABETES MELLITUS when this is either untreated or inadequately treated, as well as in starvation, persistent vomiting, and delayed anaesthetic vomiting. It also occurs in the terminal stages of glomerulonephritis (see KIDNEYS, DISEASES OF), when it is due to failure of the kidneys. A milder form of it may occur in severe fevers, particularly in children. (See also ACETONE.)
Symptoms General lassitude, vomiting, thirst, restlessness, and the presence of acetone in the urine form the earliest manifestations of the condition. In diabetes a state of COMA may ensue and the disease end fatally.
Treatment The underlying condition must always be treated: for example, if the acidosis is due to diabetes mellitus then insulin must be given. Sodium bicarbonate (see SODIUM) is rarely necessary for diabetic ketoacidosis; if it is used, it is invariably now given intravenously. Acidosis might be treated with oral sodium bicarbonate in cases of chronic renal failure. Anaesthetists dislike the administration of bicarbonate to acidotic patients, since there is some evidence that it can make intracellular acidosis worse. They almost always use HYPERVENTILATION of the arti?cially ventilated patient to correct acidosis.... acidosis
Both HIV-1 and HIV-2 are predominantly sexually transmitted and both are associated with secondary opportunistic infections. However, HIV-2 seems to result in slower damage to the immune system. HIV-1 is known to mutate rapidly and has given rise to other subtypes.
HIV is thought to have occurred in humans in the 1950s, but whether or not it infected humans from another primate species is uncertain. It became widespread in the 1970s but its latency in causing symptoms meant that the epidemic was not noticed until the following decade. Although it is a sexually transmitted disease, it can also be transmitted by intravenous drug use (through sharing an infected needle), blood transfusions with infected blood (hence the importance of e?ective national blood-screening programmes), organ donation, and occupationally (see health-care workers, below). Babies born of HIV-positive mothers can be infected before or during birth, or through breast feeding.
Although HIV is most likely to occur in blood, semen or vaginal ?uid, it has been found in saliva and tears (but not sweat); however, there is no evidence that the virus can be transmitted from these two body ?uids. There is also no evidence that HIV can be transmitted by biting insects (such as mosquitoes). HIV does not survive well in the environment and is rapidly destroyed through drying.
Prevalence At the end of 2003 an estimated 42 million people globally were infected with HIV – up from 40 million two years earlier. About one-third of those with HIV/AIDS are aged 15–24 and most are unaware that they are carrying the virus. During 2003 it is estimated that 5 million adults and children worldwide were newly infected with HIV, and that 3 million adults and children died. In Africa in 2003,
3.4 million people were newly infected and 2.3 million died, with more than 28 million carrying the virus. HIV/AIDS was the leading cause of death in sub-Saharan Africa where over half of the infections were in women and 90 per cent of cases resulted from heterosexual sex. In some southern African countries, one in three pregnant women had HIV.
In Asia and the Paci?c there were 1.2 million new infections and 435,000 deaths. The area with the fastest-growing epidemic is Eastern Europe, especially the Russian Federation where in 2002 around a million people had HIV and there were an estimated 250,000 new infections, with intravenous drug use a key contributor to this ?gure. Seventy-?ve per cent of cases occurred in men, with male-to-male sexual transmission an important cause of infection, though heterosexual activity is a rising cause of infection.
At the end of 2002 the UK had an estimated 55,900 HIV-infected adults aged between 15 and 59. More than 3,600 individuals were newly diagnosed with the infection in 2000, the highest annual ?gure since the epidemic started
– in 1998 the ?gure was 2,817 and in 1999 just over 3,000 (Department of Health and Communicable Disease Surveillance Centre). The incidence of AIDS in the UK has declined sharply since the introduction of highly active antiretroviral therapy (HAART) and HIV-related deaths have also fallen: in 2002 there were 777 reported new AIDS cases and 395 deaths, compared with 1,769 and 1,719 respectively in 1995. (Sources: UNAIDS and WHO, AIDS Epidemic Update, December 2001; Public Health Laboratory Services AIDS and STD Centre Communicable Disease Surveillance and Scottish Centre for Infection and Environmental Health, Quarterly Surveillance Tables.)
Poverty is strongly linked to the spread of AIDS, for various reasons including lack of health education; lack of e?ective public-health awareness; women having little control over sexual behaviour and contraception; and, by comparison with the developed world, little or no access to antiretroviral drugs.
Pathogenesis The cellular target of HIV infection is a subset of white blood cells called T-lymphocytes (see LYMPHOCYTE) which carry the CD4 surface receptor. These so-called ‘helper T-cells’ are vital to the function of cell-mediated immunity. Infection of these cells leads to their destruction (HIV replicates at an enormous rate – 109) and over the course of several years the body is unable to generate suf?cient new cells to keep pace. This leads to progressive destruction of the body’s immune capabilities, evidenced clinically by the development of opportunistic infection and unusual tumours.
Monitoring of clinical progression It is possible to measure the number of viral particles present in the plasma. This gives an accurate guide to the likely progression rate, which will be slow in those individuals with fewer than 10,000 particles per ml of plasma but progressively more rapid above this ?gure. The main clinical monitoring of the immune system is through the numbers of CD4 lymphocytes in the blood. The normal count is around 850 cells per ml and, without treatment, eventual progression to AIDS is likely in those individuals whose CD4 count falls below 500 per ml. Opportunistic infections occur most frequently when the count falls below 200 per ml: most such infections are treatable, and death is only likely when the CD4 count falls below 50 cells per ml when infection is developed with organisms that are di?cult to treat because of their low intrinsic virulence.
Simple, cheap and highly accurate tests are available to detect HIV antibodies in the serum. These normally occur within three months of infection and remain the cornerstone of the diagnosis.
Clinical features Most infected individuals have a viral illness some three weeks after contact with HIV. The clinical features are often non-speci?c and remain undiagnosed but include a ?ne red rash, large lymph nodes, an in?uenza-like illness, cerebral involvement and sometimes the development of opportunistic infections. The antibody test may be negative at this stage but there are usually high levels of virus particles in the blood. The antibody test is virtually always positive within three months of infection. HIV infection is often subsequently asymptomatic for a period of ten years or more, although in most patients progressive immune destruction is occurring during this time and a variety of minor opportunistic infections such as HERPES ZOSTER or oral thrush (see CANDIDA) do occur. In addition, generalised LYMPHADENOPATHY is present in a third of patients and some suffer from severe malaise, weight loss, night sweats, mild fever, ANAEMIA or easy bruising due to THROMBOCYTOPENIA.
The presentation of opportunistic infection is highly variable but usually involves either the CENTRAL NERVOUS SYSTEM, the gastrointestinal tract or the LUNGS. Patients may present with a sudden onset of a neurological de?cit or EPILEPSY due to a sudden onset of a STROKE-like syndrome, or epilepsy due to a space-occupying lesion in the brain – most commonly TOXOPLASMOSIS. In late disease, HIV infection of the central nervous system itself may produce progressive memory loss, impaired concentration and mental slowness called AIDS DEMENTIA. A wide variety of opportunistic PROTOZOA or viruses produces DYSPHAGIA, DIARRHOEA and wasting. In the respiratory system the commonest opportunistic infection associated with AIDS, pneumonia, produces severe shortness of breath and sometimes CYANOSIS, usually with a striking lack of clinical signs in the chest.
In very late HIV infection, when the CD4 count has fallen below 50 cells per ml, infection with CYTOMEGALOVIRUS may produce progressive retinal necrosis (see EYE, DISORDERS OF) which will lead to blindness if untreated, as well as a variety of gastrointestinal symptoms. At this stage, infection with atypical mycobacteria is also common, producing severe anaemia, wasting and fevers. The commonest tumour associated with HIV is Kaposi’s sarcoma which produces purplish skin lesions. This and nonHodgkin’s lymphoma (see LYMPHOMA), which is a hundred times more frequent among HIV-positive individuals than in the general population, are likely to be associated with or caused by opportunistic viral infections.
Prevention There is, as yet, no vaccine to prevent HIV infection. Vaccine development has been hampered
by the large number of new HIV strains generated through frequent mutation and recombination.
because HIV can be transmitted as free virus and in infected cells.
because HIV infects helper T-cells – the very cells involved in the immune response. There are, however, numerous research pro
grammes underway to develop vaccines that are either prophylactic or therapeutic. Vaccine-development strategies have included: recombinant-vector vaccines, in which a live bacterium or virus is genetically modi?ed to carry one or more of the HIV genes; subunit vaccines, consisting of small regions of the HIV genome designed to induce an immune response without infection; modi?ed live HIV, which has had its disease-promoting genes removed; and DNA vaccines – small loops of DNA (plasmids) containing viral genes – that make the host cells produce non-infectious viral proteins which, in turn, trigger an immune response and prime the immune system against future infection with real virus.
In the absence of an e?ective vaccine, preventing exposure remains the chief strategy in reducing the spread of HIV. Used properly, condoms are an extremely e?ective method of preventing exposure to HIV during sexual intercourse and remain the most important public-health approach to countering the further acceleration of the AIDS epidemic. The spermicide nonoxynol-9, which is often included with condoms, is known to kill HIV in vitro; however, its e?ectiveness in preventing HIV infection during intercourse is not known.
Public-health strategies must be focused on avoiding high-risk behaviour and, particularly in developing countries, empowering women to have more control over their lives, both economically and socially. In many of the poorer regions of the world, women are economically dependent on men and refusing sex, or insisting on condom use, even when they know their partners are HIV positive, is not a straightforward option. Poverty also forces many women into the sex industry where they are at greater risk of infection.
Cultural problems in gaining acceptance for universal condom-use by men in some developing countries suggests that other preventive strategies should also be considered. Microbicides used as vaginal sprays or ‘chemical condoms’ have the potential to give women more direct control over their exposure risk, and research is underway to develop suitable products.
Epidemiological studies suggest that male circumcision may o?er some protection against HIV infection, although more research is needed before this can be an established public-health strategy. Globally, about 70 per cent of infected men have acquired the virus through unprotected vaginal sex; in these men, infection is likely to have occurred through the penis with the mucosal epithelia of the inner surface of the foreskin and the frenulum considered the most likely sites for infection. It is suggested that in circumcised men, the glans may become keratinised and thus less likely to facilitate infection. Circumcision may also reduce the risk of lesions caused by other sexually transmitted disease.
Treatment AIDS/HIV treatment can be categorised as speci?c therapies for the individual opportunistic infections – which ultimately cause death – and highly active antiretroviral therapy (HAART) designed to reduce viral load and replication. HAART is also the most e?ective way of preventing opportunistic infections, and has had a signi?cant impact in delaying the onset of AIDS in HIV-positive individuals in developed countries.
Four classes of drugs are currently in use. Nucleoside analogues, including ZIDOVUDINE and DIDANOSINE, interfere with the activity of the unique enzyme of the retrovirus reverse transcriptase which is essential for replication. Nucleotide analogues, such as tenofovir, act in the same way but require no intracellular activation. Non-nucleoside reverse transcriptase inhibitors, such as nevirapine and EFAVIRENZ, act by a di?erent mechanism on the same enzyme. The most potent single agents against HIV are the protease inhibitors, such as lopinavir, which render a unique viral enzyme ineffective. These drugs are used in a variety of combinations in an attempt to reduce the plasma HIV viral load to below detectable limits, which is achieved in approximately 90 per cent of patients who have not previously received therapy. This usually also produces a profound rise in CD4 count. It is likely, however, that such treatments need to be lifelong – and since they are associated with toxicities, long-term adherence is di?cult. Thus the optimum time for treatment intervention remains controversial, with some clinicians believing that this should be governed by the viral load rising above 10,000 copies, and others that it should primarily be designed to prevent the development of opportunistic infections – thus, that initiation of therapy should be guided more by the CD4 count.
It should be noted that the drug regimens have been devised for infection with HIV-1; it is not known how e?ective they are at treating infection with HIV-2.
HIV and pregnancy An HIV-positive woman can transmit the virus to her fetus, with the risk of infection being particularly high during parturition; however, the risk of perinatal HIV transmission can be reduced by antiviral drug therapy. In the UK, HIV testing is available to all women as part of antenatal care. The bene?ts of antenatal HIV testing in countries where antiviral drugs are not available are questionable. An HIV-positive woman might be advised not to breast feed because of the risks of transmitting HIV via breastmilk, but there may be a greater risk associated with not breast feeding at all. Babies in many poor communities are thought to be at high risk of infectious diseases and malnutrition if they are not breast fed and may thus be at greater overall risk of death during infancy.
Counselling Con?dential counselling is an essential part of AIDS management, both in terms of supporting the psychological wellbeing of the individual and in dealing with issues such as family relations, sexual partners and implications for employment (e.g. for health-care workers). Counsellors must be particularly sensitive to culture and lifestyle issues. Counselling is essential both before an HIV test is taken and when the results are revealed.
Health-care workers Health-care workers may be at risk of occupational exposure to HIV, either through undertaking invasive procedures or through accidental exposure to infected blood from a contaminated needle (needlestick injury). Needlestick injuries are frequent in health care – as many as 600,000 to 800,000 are thought to occur annually in the United States. Transmission is much more likely where the worker has been exposed to HIV through a needlestick injury or deep cut with a contaminated instrument than through exposure of mucous membranes to contaminated blood or body ?uids. However, even where exposure occurs through a needlestick injury, the risk of seroconversion is much lower than with a similar exposure to hepatitis C or hepatitis B. A percutaneous exposure to HIV-infected blood in a health-care setting is thought to carry a risk of about one infection per 300 injuries (one in 1,000 for mucous-membrane exposure), compared with one in 30 for hepatitis C, and one in three for hepatitis B (when the source patient is e-antigen positive).
In the event of an injury, health-care workers are advised to report the incident immediately where, depending on a risk assessment, they may be o?ered post-exposure prophylaxis (PEP). They should also wash the contaminated area with soap and water (but without scrubbing) and, if appropriate, encourage bleeding at the site of injury. PEP, using a combination of antiretroviral drugs (in a similar regimen to HAART – see above), is thought to greatly reduce the chances of seroconversion; it should be commenced as soon as possible, preferably within one or two hours of the injury. Although PEP is available, safe systems of work are considered to o?er the greatest protection. Double-gloving (latex gloves remove much of the blood from the surface of the needle during a needlestick), correct use of sharps containers (for used needles and instruments), avoiding the resheathing of used needles, reduction in the number of blood samples taken from a patient, safer-needle devices (such as needles that self-blunt after use) and needleless drug administration are all thought to reduce the risk of exposure to HIV and other blood-borne viruses. Although there have been numerous cases of health-care workers developing HIV through occupational exposure, there is little evidence of health-care workers passing HIV to their patients through normal medical procedures.... aids/hiv
Habitat: The sub-tropical Himalayas of Kumaon and Nepal; cultivated in Andhra Pradesh.
Ayurvedic: Gandira (Achyranthes aquatica Br. is also equated with Gandira). (Doubtful synonym.)Folk: Garmar (Gujarat), Gurmal.Action: Root and leaf—spasmolytic, antithrombotic, anti-inflammatory, lipolytic.
In experimental amoebiasis of rats, the root powder and ethanolic extract showed amoebicidal activity against Entamoeba histolytica.An alcoholic extract of the roots and essential oil from it, were found to inhibit passive cutaneous anaphylaxis in the mouse and rat.The plant produces the labdane diterpenoid, forskolin in its tuberous roots.Forskolin was discovered during a screening of medicinal plants by Central Drug Research Institute, Luc- know, India, in 1974. (Planta Medica, 1985, 51, 473-477.) The screening revealed the presence of a hypoten- sive and spasmolytic principle, named coleonol (later the name was changed to forskolin). The basic mechanism of forskolin is the activation of an enzyme, adenylate cyclase, which increases the amount of cyclic adeno- sine monophosphate (cAMP) in cells. Raised intracellular cAMP level exhibits following physiological effects : inhibition of platelet activation and degranulation; inhibition of mast cell degranualation and histamine release; relaxation of the arteries and other smooth muscles; increased insulin secretion; increased thyroid function; increased lipolysis.Forskolin, in clinical studies, reduced intraocular pressure when it was applied to the eyes for treating glaucoma. It has been shown to be a direct cerebral vasodilator. It has also been studied as a possible bron- chodilator (in the treatment of asthma) and has been shown to effectively reverse methacholine-induced broncho constriction in extrinsic asthmatics.Standardized Coleus extracts containing forskolin (18% in 50 mg) find application in weight-loss programmes. (Michael T. Murray.)Studies on forskolin and some 50 derivatives of the compound indicate that the natural product is more active than the analogs prepared from it.The wild var. is known as Kaffir Potato.... coleus barbatusDIABETES INSIPIDUS, a condition characterised by the passing of a large volume of URINE every day, is due to lack of the antidiuretic hormone (see VASOPRESSIN). Enhanced production of the ADRENOCORTICOTROPHIC HORMONE (ACTH) leads to CUSHING’S SYNDROME. Excessive production of PROLACTIN by micro or macro adenomas (benign tumours) leads to hyperprolactinaemia and consequent AMENORRHOEA and GALACTORRHOEA. Some adenomas do not produce any hormone but cause effects by damaging the pituitary cells and inhibiting their hormone production.
The most sensitive cells to extrinsic pressure are the gonadotrophin-producing cells and the growth-hormone producing cells, so that if the tumour occurs in childhood, growth hormone will be suppressed and growth will slow. Gonadotrophin hormone suppression will prevent the development of puberty and, if the tumour occurs after puberty, will result in amenorrhoea in the female and lack of LIBIDO in both sexes. The thyroid-stimulating hormone cells are the next to suffer and the pressure effects on these cells will result in hypothyroidism (see under THYROID GLAND, DISEASES OF).
Fortunately the ACTH-producing cells are the most resistant to extrinsic pressure and this is teleologically sound as ACTH is the one pituitary hormone that is essential to life. However, these cells can suffer damage from intracellular tumours, and adrenocortical insu?ciency is not uncommon.
Information about these disorders may be obtained from the Pituitary Foundation.... pituitary-linked disorders
M. tuberculosis is by far the most common species responsible for infections of the lung. Other mycobacteria that infect the lung are variously described as atypical, anonymous, or *opportunistic – the favoured term since they usually require pre-existing lung damage or a defect in the patient’s immunity before they can give rise to infection. The opportunistic mycobacteria that most commonly cause lung infections are M. kansacii, M. xenopi, M. malmoense, and a group known as the MAI complex (M. avium, M. intracellulare). Infections caused by all these organisms can mimic pulmonary tuberculosis but are much more difficult to treat since they are resistant to many of the antituberculosis drugs. The MAI organisms are particularly likely to cause superimposed infection in cases of AIDS.... mycobacterium
Among the smallest and simplest microorganisms are the viruses. First described as ?lterable agents, and ranging in size from 20–30 nm to 300 nm, they may be directly visualised only by electron microscopy. They consist of a core of deoxyribonucleic or ribonucleic acid (DNA or RNA) within a protective protein coat, or capsid, whose subunits confer a geometric symmetry. Thus viruses are usually cubical (icosahedral) or helical; the larger viruses (pox-, herpes-, myxo-viruses) may also have an outer envelope. Their minimal structure dictates that viruses are all obligate parasites, relying on living cells to provide essential components for their replication. Apart from animal and plant cells, viruses may infect and replicate in bacteria (bacteriophages) or fungi (mycophages), which are damaged in the process.
Bacteria are larger (0·01–5,000 µm) and more complex. They have a subcellular organisation which generally includes DNA and RNA, a cell membrane, organelles such as ribosomes, and a complex and chemically variable cell envelope – but, unlike EUKARYOTES, no nucleus. Rickettsiae, chlamydia, and mycoplasmas, once thought of as viruses because of their small size and absence of a cell wall (mycoplasma) or major wall component (chlamydia), are now acknowledged as bacteria; rickettsiae and chlamydia are intracellular parasites of medical importance. Bacteria may also possess additional surface structures, such as capsules and organs of locomotion (?agella) and attachment (?mbriae and stalks). Individual bacterial cells may be spheres (cocci); straight (bacilli), curved (vibrio), or ?exuous (spirilla) rods; or oval cells (coccobacilli). On examination by light microscopy, bacteria may be visible in characteristic con?gurations (as pairs of cocci [diplococci], or chains [streptococci], or clusters); actinomycete bacteria grow as ?laments with externally produced spores. Bacteria grow essentially by increasing in cell size and dividing by ?ssion, a process which in ideal laboratory conditions some bacteria may achieve about once every 20 minutes. Under natural conditions, growth is usually much slower.
Eukaryotic micro-organisms comprise fungi, algae, and protozoa. These organisms are larger, and they have in common a well-developed internal compartmentation into subcellular organelles; they also have a nucleus. Algae additionally have chloroplasts, which contain photosynthetic pigments; fungi lack chloroplasts; and protozoa lack both a cell wall and chloroplasts but may have a contractile vacuole to regulate water uptake and, in some, structures for capturing and ingesting food. Fungi grow either as discrete cells (yeasts), multiplying by budding, ?ssion, or conjugation, or as thin ?laments (hyphae) which bear spores, although some may show both morphological forms during their life-cycle. Algae and protozoa generally grow as individual cells or colonies of individuals and multiply by ?ssion.
Micro-organisms of medical importance include representatives of the ?ve major microbial groups that obtain their essential nutrients at the expense of their hosts. Many bacteria and most fungi, however, are saprophytes (see SAPROPHYTE), being major contributors to the natural cycling of carbon in the environment and to biodeterioration; others are of ecological and economic importance because of the diseases they cause in agricultural or horticultural crops or because of their bene?cial relationships with higher organisms. Additionally, they may be of industrial or biotechnological importance. Fungal diseases of humans tend to be most important in tropical environments and in immuno-compromised subjects.
Pathogenic (that is, disease-causing) microorganisms have special characteristics, or virulence factors, that enable them to colonise their hosts and overcome or evade physical, biochemical, and immunological host defences. For example, the presence of capsules, as in the bacteria that cause anthrax (Bacillus anthracis), one form of pneumonia (Streptococcus pneumoniae), scarlet fever (S. pyogenes), bacterial meningitis (Neisseria meningitidis, Haemophilus in?uenzae) is directly related to the ability to cause disease because of their antiphagocytic properties. Fimbriae are related to virulence, enabling tissue attachment – for example, in gonorrhoea (N. gonorrhoeae) and cholera (Vibrio cholerae). Many bacteria excrete extracellular virulence factors; these include enzymes and other agents that impair the host’s physiological and immunological functions. Some bacteria produce powerful toxins (excreted exotoxins or endogenous endotoxins), which may cause local tissue destruction and allow colonisation by the pathogen or whose speci?c action may explain the disease mechanism. In Staphylococcus aureus, exfoliative toxin produces the staphylococcal scalded-skin syndrome, TSS toxin-1 toxic-shock syndrome, and enterotoxin food poisoning. The pertussis exotoxin of Bordetella pertussis, the cause of whooping cough, blocks immunological defences and mediates attachment to tracheal cells, and the exotoxin produced by Corynebacterium diphtheriae causes local damage resulting in a pronounced exudate in the trachea.
Viruses cause disease by cellular destruction arising from their intracellular parasitic existence. Attachment to particular cells is often mediated by speci?c viral surface proteins; mechanisms for evading immunological defences include latency, change in viral antigenic structure, or incapacitation of the immune system – for example, destruction of CD 4 lymphocytes by the human immunode?ciency virus.... microbiology
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